Next-generation nanocrystals of phytochemicals: overcoming bioavailability challenges and enabling targeted therapeutics.

Abstract

Phytochemicals have gained remarkable attention because of their broad-spectrum therapeutic activities, including antioxidant, anti-inflammatory, antimicrobial, neuroprotective, and anticancer effects. Despite their pharmacological potential, the clinical translation of many phytochemicals remains limited due to poor aqueous solubility, low permeability, rapid metabolism, and inadequate bioavailability. Nanocrystal technology has emerged as a promising strategy to overcome these challenges by enhancing the dissolution rate, saturation solubility, cellular uptake, and systemic exposure of poorly water-soluble phytochemicals. Nanocrystals offer several advantages, including high drug-loading capacity, reduced carrier-associated toxicity, improved stability, and the possibility of surface functionalization for targeted delivery. This review highlights the evolution of nanocrystal technologies, including Dissocubes®, Nanopure®, H96, H42, H69, and NanoEdge®, along with their applications in the fabrication of phytochemical nanocrystals. Furthermore, the review discusses regulatory-approved and investigational phytochemicals such as paclitaxel, quercetin, artemisinin, silymarin, and cannabidiol, and various unregulated phytochemicals formulated into nanocrystals for improved therapeutic efficacy. Special emphasis has been placed on targeted delivery approaches through ligand surface modification for enhanced tissue accumulation and reduced off-target toxicity. Additionally, the article outlines the current regulatory perspectives, manufacturing challenges, scale-up limitations, and safety considerations associated with nanocrystal-based therapeutics.